Mitochondrial voltage-dependent anion channel is responsible for paraquat cytotoxicity.

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Paraquat is an herbicide that forms reactive oxygen metabolites, which are toxic to humans. With respect to the cytotoxicmechanisms, we identified a NADH-quinone oxidoreductasem activity located on the mitochondria and propose the participationof a voltage-dependent anion channel, VDAC.When isolated rat mitochondria were incubated with NADH and paraquat, H_2O_2 was produced by NADH-quinoneoxidoreductasem activity of the outer membrane and the mitochondria were damaged. These changes were suppressed bybenzoquinone, 4,4'-diisothiocyanatostilbene-2,29-disulfic acid and anti-VDAC1 antibody. NADH-quinone oxidoreductasemactivity was located by zymography at the 500kDa band on native-polyacrylamide electrophoresis, and it contained VDAC protein in a Western blot. VDAC1-overexpressed HeLa cells treated with paraquat produced more intracellular H_2O_2 thancontrols and were more sensitive to paraquat. In contrast, mitochondria in VDAC1 knockdown cells did not produce H_2O_2 andhad a higher survival rate after exposure to paraquat. The results indicate that mitochondrial VDAC protein was associated with reactive oxygen species that mediated paraquat toxicity.